The overall goal of this project is to test the hypothesis that acromegaly is a disorder of a hypothalamic origin resulting from an augmented secretion of hypothalamic growth hormone- releasing factor (GRF). This hypothesis will be approached in several ways. Specifically, we plan: 1) To perform a detailed analysis of the pulsatile pattern of growth hormone secretion and to assess pituitary sensitivity to GRF in patients with acromegaly; 2) To study effects of pulsatile GRF administration upon GH secretion in normal controls and in patients with isolated GH deficiency (IGHD); 3) To explore the possibility that the feedback inhibition of growth hormone secretion by somatomedin C is defective in patients with acromegaly; 4) To assess the integrity of endogenous hypothalamic somatostatin secretion in acromegalic patients. The principal approaches to these objectives will include: a) Establishment of uniform criteria for the detection of GH secretory episodes (pulses); b) Indirect assessment of hypothalamic regulatory mechanisms of GH secretion via detailed estimation of the GH secretory patterns in normal versus acromegalic subjects; utilizing the aforementioned criteria; c) Establishment of the dose of exogenous GRF necessary to reproduce the spontaneous GH pulse amplitude in normal vs. acromegalic subjects; d) Examining the effects of the fasting- induced fall in somatomedin C generation upon the GH secretory pattern in patients with acromegaly; e) Administration of GRF to normal individuals and to patients with IGHD in a manner (dose/frequency) reproducing the endogenous GH secretion in patients with acromegaly; f) Studies of endogenous hypothalamic SRIF secretion. Normal adult men and women and patients with acromegaly or IGHD will participate in detailed protocols performed in the Clinical Research Center at the University of Michigan Hospital. Established radioimmunoassays will be used for serial hormone determinations. These studies will provide a more detailed understanding of the physiology of human GH secretion in normal and pathological conditions, and should allow new insights into the mechanisms of GH hypersecretion.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29DK038449-01
Application #
3462608
Study Section
Endocrinology Study Section (END)
Project Start
1987-09-01
Project End
1992-08-31
Budget Start
1987-09-01
Budget End
1988-08-31
Support Year
1
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Jaffe, C A; DeMott-Friberg, R; Barkan, A L (1996) Endogenous growth hormone (GH)-releasing hormone is required for GH responses to pharmacological stimuli. J Clin Invest 97:934-40
Jaffe, C A; Turgeon, D K; Friberg, R D et al. (1995) Nocturnal augmentation of growth hormone (GH) secretion is preserved during repetitive bolus administration of GH-releasing hormone: potential involvement of endogenous somatostatin--a clinical research center study. J Clin Endocrinol Metab 80:3321-6
Ho, P J; Gesundheit, N; Wong, W L et al. (1995) Dynamic changes of growth hormone-binding protein concentrations in normal men and patients with acromegaly: effects of short-term fasting. Metabolism 44:667-72
Ho, P J; Jaffe, C A; Friberg, R D et al. (1994) Persistence of rapid growth hormone (GH) pulsatility after successful removal of GH-producing pituitary tumors. J Clin Endocrinol Metab 78:1403-10
Bermann, M; Jaffe, C A; Tsai, W et al. (1994) Negative feedback regulation of pulsatile growth hormone secretion by insulin-like growth factor I. Involvement of hypothalamic somatostatin. J Clin Invest 94:138-45
Hu, Z; Friberg, R D; Barkan, A L (1993) Ontogeny of GH mRNA and GH secretion in male and female rats: regulation by GH-releasing hormone. Am J Physiol 265:E236-42
Alster, D K; Bowers, C Y; Jaffe, C A et al. (1993) The growth hormone (GH) response to GH-releasing peptide (His-DTrp-Ala-Trp-DPhe-Lys-NH2), GH-releasing hormone, and thyrotropin-releasing hormone in acromegaly. J Clin Endocrinol Metab 77:842-5
Jaffe, C A; Friberg, R D; Barkan, A L (1993) Suppression of growth hormone (GH) secretion by a selective GH-releasing hormone (GHRH) antagonist. Direct evidence for involvement of endogenous GHRH in the generation of GH pulses. J Clin Invest 92:695-701
Ho, P J; Kletter, G B; Hopwood, N J et al. (1993) Somatostatin withdrawal alone is an ineffective generator of pulsatile growth hormone release in man. Acta Endocrinol (Copenh) 129:414-8
Jaffe, C A; Ho, P J; Demott-Friberg, R et al. (1993) Effects of a prolonged growth hormone (GH)-releasing peptide infusion on pulsatile GH secretion in normal men. J Clin Endocrinol Metab 77:1641-7

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